Preclinical Evaluation of eFT226, a Novel, Potent and Selective eIF4A Inhibitor with Anti-Tumor Activity in B-Cell Malignancies

Translational control of oncoprotein expression has been implicated in the pathogenesis of multiple solid tumors and hematological malignancies. Protein synthesis is tightly regulated largely at the initiation stage through the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, an RNA helicase, is an essential component of the translation initiation complex and selectively regulates a subset of mRNAs based on the sequence and structure of the 5'-untranslated region (UTR). B-cell receptor signaling activates eIF4A resulting in the selective upregulation of oncogenes involved in cell proliferation, survival and metastasis. B-cell malignancies are often associated with dysregulation of oncogenes or anti-apoptotic proteins (e.g., c-MYC, CCND1/3, BCL2 and MCL-1) that contain structured 5'-UTRs and require enhanced eIF4A activity for translation.

eFT226 is a potent and selective eIF4A inhibitor that promotes eIF4A binding to specific mRNA sequences and interferes with the assembly of the eIF4F initiation complex. eFT226 selectively inhibits translation of mRNAs containing longer 5'-UTRs, an increased frequency of uORFs (upstream open reading frame), and polypurine and/or G-quadraplex recognition motifs. The sequence dependency of eFT226 translational inhibition was evaluated in an in vitro translation assay demonstrating potent inhibition of reporter constructs containing a polypurine motif in the 5'-UTR (IC₅₀ ~2 nM). Direct binding studies also confirmed the formation of a stable ternary complex between eFT226, eIF4A and mRNA oligonucleotides containing polypurine motifs. This results in selective and translational downregulation of a subset of genes that are important for tumor growth and survival. eFT226 showed potent anti-proliferative activity (EC₅₀ < 15 nM) and an induction of apoptosis against a panel of B-cell lymphoma cell lines. Sensitivity to eFT226 was associated with dose-dependent decreases in the oncogenic drivers c-MYC, CCND1/3, BCL2 or MCL-1 in ABC (activated B-Cell) and GCB (germinal center B-cell) DLBCL (Diffuse Large B-cell Lymphoma) subtypes and Burkitt's lymphoma. eFT226 has good pharmacokinetic properties that result in potent in vivo efficacy with ≤ 1 mg/kg/week IV administration. Preclinical efficacy studies using eFT226 showed in vivo activity across hematological tumor models suggesting that eFT226 may be active in tumor types where overexpression or amplification of oncogenes such as c-MYC, CCND1/3, BCL2 or MCL-1 play a role in disease pathogenesis. These results demonstrate the potential of eFT226 for the treatment of B-cell malignancies. Clinical trials in patients with hematological and other malignancies are planned.